Adverse events in people taking macrolide antibiotics versus placebo for any indication

BACKGROUND: Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment-specific, rather than disease-specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. OBJECTIVES:To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. SELECTION CRITERIA: We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide-resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta-analysis when three or more included studies reported a specific adverse event. MAIN RESULTS: We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin.Most studies (89%) reported some adverse events or at least stated that no adverse events were observed.Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low-quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low-quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate-quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate-quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate-quality evidence) were also reported more often in participants taking macrolides compared to placebo.The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000.The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting.There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration.Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; Iand#178; = 46%; low-quality evidence).Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; Iand#178; = 0%; low-quality evidence).We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low-quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low-quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low-quality evidence) compared to placebo.We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo.Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate-quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate-quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate-quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non-significant.There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; Iand#178; = 11%; low-quality evidence).Only 24 studies (13%) provided useful data on macrolide-resistant bacteria. Macrolide-resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent.Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. AUTHORS' CONCLUSIONS: The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance.</p

Etude de cellules solaires en silicium cristallin à l'échelle nanométrique à l'aide de techniques de microscopie à sonde locale

This thesis focuses on the investigation of crystalline silicon solar cells at the nano-scale using scanning probe microscopy (SPM) techniques. In particular, we chose to investigate electrical properties at the nano-scale using two SPM techniques: Kelvin Probe Force Microscopy (KPFM) and Conducting Probe Atomic Force Microscopy (CP-AFM).First, we highlight the strengths and weaknesses of both these techniques compared to electron microscopy techniques, which can also help investigate electrical properties at the nano-scale. This comprehensive comparison enables to identify measurements where KPFM and CP-AFM are particularly adequate. These measurements are divided in two categories: material investigation and devices investigation.Then, we focus on materials investigation at the nano-scale using SPM techniques. We first present doping measurements at the nano-scale using an advanced CP-AFM technique called Resiscope. We prove that this technique could detect doping changes in the range 1015 and 1020 atoms.cm-3 with a nano-scale resolution and a high signal/noise ratio. Then, we highlight decay time measurements on passivated crystalline silicon wafers using KPFM. Measurements are performed on the unpassivated cross-section. We show that, even though the cross-section is not passivated, decay times measurements obtained with KPFM are in good agreement with lifetimes measured by microwave photoconductivity decay.Subsequently, we focus on device measurements. Using KPFM, we investigate two different crystalline silicon solar cell architectures: epitaxial silicon (epi-Si) solar cells and interdigitated back contact (IBC) heterojunction solar cells. In particular, we focus on measurements on devices under operating conditions. We first study the influence of the applied electrical bias. We study the sensitivity of surface potential to electrical bias and we show that diode and resistance effects can be detected at the nano-scale. KPFM measurements are compared to scanning electron microscopy (SEM) measurements in the same conditions since SEM is also sensitive to surface potential. We show that KPFM measurements on the cross-section of epi-Si solar cells can help detect electric field changes with electrical bias. Besides, if the electrical bias is frequency modulated, we show that lifetime measurements can be performed on the cross-section of epi-Si solar cells and can help detect limiting interfaces and layers. Then, we study the influence of illumination on KPFM and CP-AFM measurements. We perform photovoltage and photocurrent measurements on the cross-section of epi-Si solar under different values of illumination intensity and illumination wavelength. We show a good sensitivity of KPFM measurements to illumination. However, we show that measurements for different wavelengths at a given open circuit voltage, are not correlated with the internal quantum efficiency, as we could have expected.Finally, we summarize our work in a table showing the impact of strengths and weaknesses of the techniques for the different measurements highlighted. From this table, we imagine an “ideal” microscopy setup to investigate crystalline silicon solar cells in a reliable, versatile and accurate way. We propose investigations of interest that could be carried out using this “ideal” setup.Cette thèse s’intéresse à l’analyse de cellules silicium cristallin à l’échelle nanométrique, à l’aide de techniques de microscopie à sonde locale (SPM). En particulier, nous avons choisi d’analyser les propriétés électriques à l’échelle locale, grâce à deux techniques SPM : la microcopie à sonde de Kelvin (KPFM) et la microscopie à force atomique à sonde conductrice (CP-AFM).Tout d’abord, nous présentons les forces et faiblesses de ces deux techniques, comparées à la microscopie électronique, qui permet également d’analyser les propriétés électrique à l’échelle nanométrique. Cette comparaison approfondie nous permet d’identifier des mesures où le KPFM et le CP-AFM sont particulièrement adéquat et peuvent apporter de la valeur. Ces mesures sont divisées en deux catégories : les analyses matériaux et les analyses dispositifs.Ensuite, nous nous focalisons sur les analyses matériaux à l’échelle nanométrique. Nous présentons d’abord des mesures de dopage à l’échelle nanométrique, à l’aide d’une technique avancée de CP-AFM, appelée Resiscope. Nous montrons que cette technique peut détecter des changements de dopage dans la gamme 1015 à 1020 atomes.cm-3, avec une résolution nanométrique et un bon ratio signal/bruit. Puis, nous présentons des mesures de durée de décroissance sur des wafers silicium cristallin passivés. Les mesures sont réalisées sur la tranche non-passivée des échantillons. Nous montrons que, même si la tranche n’est pas passivée, les durées de décroissance obtenue par KPFM ont une bonne corrélation avec les temps de vie des wafers mesurées par décroissance de la photoconductivité détectée par micro-ondes.Par la suite, nous nous concentrons sur les analyses dispositif. A l’aide du KPFM, nous analysons deux types de cellules solaires silicium cristallin : les cellules solaires silicium épitaxié (epi-Si) et les cellules solaires hétérojonctions à contact arrière (IBC). En particulier, nous nous focalisons sur l’analyse de dispositifs en condition d’opération. Nous étudions d’abord l’influence de la tension électrique appliquée et nous montrons que les effets de résistance et de diode peuvent être détectés à l’échelle nanométrique. Les mesures de KPFM sont comparées aux mesures de microscopie électronique à balayage (SEM) dans les mêmes conditions, puisque le SEM est aussi sensible au potentiel de surface. Nous montrons que les mesures KPFM sur la tranche de cellules solaires epi-Si peuvent permettre d’étudier les changements de champ électrique avec la tension électrique appliquée. De plus, si la tension électrique est modulée en fréquence, nous montrons que des mesures de temps de vie peuvent être effectuées à l’échelle locale sur la tranche de cellules solaires epi-Si, ce qui peut permettre de détecter les interfaces limitantes. Puis, nous étudions l’influence de l’illumination sur les mesures KPFM et CP-AFM. Nous effectuons des mesures sur la tranche de cellules epi-Si sous différentes valeurs d’intensité et longueurs d’onde d’illumination. Nous montrons une bonne sensibilité des mesures KPFM à l’illumination. Cependant, nous montrons que pour différentes longueurs d’onde, à tension de circuit ouvert fixé, nos mesures ne sont pas corrélées avec les mesures de rendement quantique interne, comme nous le pensions.Enfin, nous résumons notre travail dans un tableau qui représente les forces et faiblesses des techniques pour les différentes mesures d’intérêt exposées précédemment. A partir de ce tableau, nous imaginons un setup de microscopie « idéal » qui permette d’analyser les cellules solaires de manière fiable, versatile et précise. Pour finir, nous proposons des mesures d’intérêt qui pourraient être réalisées avec ce setup « idéal »

Nanoscale Investigation of Carrier Lifetime on the Cross Section of Epitaxial Silicon Solar Cells Using Kelvin Probe Force Microscopy

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Etude sur la tranche de cellules solaires en silicium cristallin à l'échelle nanométrique à l'aide de techniques de microscopie à sonde locale

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Cross-sectional investigations on epitaxial silicon solar cells by Kelvin and Conducting Probe Atomic Force Microscopy: Effect of illumination

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Surface potential investigation on interdigitated back contact solar cells by Scanning Electron Microscopy and Kelvin Probe Force Microscopy: Effect of electrical bias

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